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Published in: Annals of Surgical Oncology 6/2014

01-06-2014 | Head and Neck Oncology

Prognostic Significance of Epithelial-Mesenchymal Transition of Extracapsular Spread Tumors in Lymph Node Metastases of Head and Neck Cancer

Authors: Won-Yong Lee, MD, Da-Yong Shin, MS, Hye Jin Kim, MS, Young-Hyeh Ko, MD, PhD, Sehoon Kim, PhD, Han-Sin Jeong, MD, PhD

Published in: Annals of Surgical Oncology | Issue 6/2014

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Abstract

Background and Purpose

The extracapsular spread (ECS) of lymph node metastasis (LNM) reflects tumor aggressiveness and is associated with poor survival and risk of distant metastasis. In this study, we aimed to explore the prognostic significance of epithelial-mesenchymal transition (EMT) of ECS tumors in LNM of head and neck cancers.

Methods

We collected LNM samples from head and neck cancer patients (follow-up >2 years) and made 20 ECS(−): ECS(+) pairs (1:2) of LNM (N = 60), matched by the primary sites and by T and N classifications. Immunostaining of cytokeratin, E-cadherin, vimentin, and CD31 were performed and quantified to determine the epithelial-mesenchymal transition percent (EMT%), defined as vimentin(+)/cytokeratin(+) area of ECS. Univariate and multivariable analyses of clinic-pathologic factors, including EMT% of ECS, were conducted to identify the significant prognosticators. In addition, the anatomical relationship between CD31 vessels and ECS tumors was analyzed.

Results

Rather than the presence of ECS in LNM, higher EMT% (>50 %) of ECS strongly correlated with the worse overall and disease-free survival and had more frequent recurrence and distant dissemination in their clinical courses. ECS tumors intermingled closely with Ki-67(−) CD31(+) non-proliferating perinodal blood vessels. Particularly, vimentin(+) ECS areas exhibited a higher density of CD31(+) perinodal vessels than did vimentin(−) ECS.

Conclusion

High EMT scores of ECS tumors in LNM predict an unfavorable prognosis and systemic dissemination more accurately than the simple presence of ECS in LNM in head and neck cancer patients.
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Literature
1.
go back to reference de Carvalho BM. Quantitative analysis of the extent of extracapsular invasion and its prognostic significance: a prospective study of 170 cases of carcinoma of the larynx and hypopharynx. Head Neck. 1998;20:16–21.CrossRef de Carvalho BM. Quantitative analysis of the extent of extracapsular invasion and its prognostic significance: a prospective study of 170 cases of carcinoma of the larynx and hypopharynx. Head Neck. 1998;20:16–21.CrossRef
2.
go back to reference Grandi C, Alloisio M, Moglia D, et al. Prognostic significance of lymphatic spread in head and neck carcinomas: therapeutic implications. Head Neck Surg. 1985;8:67–73. PubMedCrossRef Grandi C, Alloisio M, Moglia D, et al. Prognostic significance of lymphatic spread in head and neck carcinomas: therapeutic implications. Head Neck Surg. 1985;8:67–73. PubMedCrossRef
3.
go back to reference Greenberg JS, Fowler R, Gomez J, et al. Extent of extracapsular spread: a critical prognosticator in oral tongue cancer. Cancer. 2003;97:1464–70.PubMedCrossRef Greenberg JS, Fowler R, Gomez J, et al. Extent of extracapsular spread: a critical prognosticator in oral tongue cancer. Cancer. 2003;97:1464–70.PubMedCrossRef
4.
go back to reference Gruber G, Bonetti M, Nasi ML, et al. Prognostic value of extracapsular tumor spread for locoregional control in premenopausal patients with node-positive breast cancer treated with classical cyclophosphamide, methotrexate, and fluorouracil: long-term observations from International Breast Cancer Study Group Trial VI. J Clin Oncol. 2005;23:7089–97.PubMedCrossRef Gruber G, Bonetti M, Nasi ML, et al. Prognostic value of extracapsular tumor spread for locoregional control in premenopausal patients with node-positive breast cancer treated with classical cyclophosphamide, methotrexate, and fluorouracil: long-term observations from International Breast Cancer Study Group Trial VI. J Clin Oncol. 2005;23:7089–97.PubMedCrossRef
5.
go back to reference Gruber G, Cole BF, Castiglione-Gertsch M, et al. Extracapsular tumor spread and the risk of local, axillary and supraclavicular recurrence in node-positive, premenopausal patients with breast cancer. Ann Oncol. 2008;19:1393–401.PubMedCentralPubMedCrossRef Gruber G, Cole BF, Castiglione-Gertsch M, et al. Extracapsular tumor spread and the risk of local, axillary and supraclavicular recurrence in node-positive, premenopausal patients with breast cancer. Ann Oncol. 2008;19:1393–401.PubMedCentralPubMedCrossRef
6.
go back to reference Heide J, Krull A, Berger J. Extracapsular spread of nodal metastasis as a prognostic factor in rectal cancer. Int J Radiat Oncol Biol Phys. 2004;58:773–8.PubMedCrossRef Heide J, Krull A, Berger J. Extracapsular spread of nodal metastasis as a prognostic factor in rectal cancer. Int J Radiat Oncol Biol Phys. 2004;58:773–8.PubMedCrossRef
7.
go back to reference Johnson JT, Barnes EL, Myers EN, Schramm VL, Jr., Borochovitz D, Sigler BA. The extracapsular spread of tumors in cervical node metastasis. Arch Otolaryngol. 1981;107:725–9.PubMedCrossRef Johnson JT, Barnes EL, Myers EN, Schramm VL, Jr., Borochovitz D, Sigler BA. The extracapsular spread of tumors in cervical node metastasis. Arch Otolaryngol. 1981;107:725–9.PubMedCrossRef
8.
go back to reference Johnson JT, Myers EN, Bedetti CD, Barnes EL, Schramm VL, Jr., Thearle PB. Cervical lymph node metastases. Incidence and implications of extracapsular carcinoma. Arch Otolaryngol. 1985;111:534–7.PubMedCrossRef Johnson JT, Myers EN, Bedetti CD, Barnes EL, Schramm VL, Jr., Thearle PB. Cervical lymph node metastases. Incidence and implications of extracapsular carcinoma. Arch Otolaryngol. 1985;111:534–7.PubMedCrossRef
9.
go back to reference Jose J, Coatesworth AP, Johnston C, MacLennan K. Cervical node metastases in squamous cell carcinoma of the upper aerodigestive tract: the significance of extracapsular spread and soft tissue deposits. Head Neck. 2003;25:451–6.PubMedCrossRef Jose J, Coatesworth AP, Johnston C, MacLennan K. Cervical node metastases in squamous cell carcinoma of the upper aerodigestive tract: the significance of extracapsular spread and soft tissue deposits. Head Neck. 2003;25:451–6.PubMedCrossRef
10.
go back to reference Liao CT, Wang HM, Chang JT, et al. Analysis of risk factors for distant metastases in squamous cell carcinoma of the oral cavity. Cancer. 2007;110:1501–8.PubMedCrossRef Liao CT, Wang HM, Chang JT, et al. Analysis of risk factors for distant metastases in squamous cell carcinoma of the oral cavity. Cancer. 2007;110:1501–8.PubMedCrossRef
11.
go back to reference Metindir J, Bilir Dilek G. Evaluation of prognostic significance in extracapsular spread of pelvic lymph node metastasis in patients with cervical cancer. Eur J Gynaecol Oncol. 2008;29:476–8.PubMed Metindir J, Bilir Dilek G. Evaluation of prognostic significance in extracapsular spread of pelvic lymph node metastasis in patients with cervical cancer. Eur J Gynaecol Oncol. 2008;29:476–8.PubMed
12.
go back to reference Shaw RJ, Lowe D, Woolgar JA, et al. Extracapsular spread in oral squamous cell carcinoma. Head Neck. 2010;32:714–22.PubMed Shaw RJ, Lowe D, Woolgar JA, et al. Extracapsular spread in oral squamous cell carcinoma. Head Neck. 2010;32:714–22.PubMed
13.
go back to reference van der Velden J, van Lindert AC, Lammes FB, et al. Extracapsular growth of lymph node metastases in squamous cell carcinoma of the vulva. The impact on recurrence and survival. Cancer. 1995;75:2885–90.PubMedCrossRef van der Velden J, van Lindert AC, Lammes FB, et al. Extracapsular growth of lymph node metastases in squamous cell carcinoma of the vulva. The impact on recurrence and survival. Cancer. 1995;75:2885–90.PubMedCrossRef
14.
go back to reference Richard JM, Sancho-Garnier H, Micheau C, Saravane D, Cachin Y. Prognostic factors in cervical lymph node metastasis in upper respiratory and digestive tract carcinomas: study of 1,713 cases during a 15-year period. Laryngoscope. 1987;97:97–101.PubMedCrossRef Richard JM, Sancho-Garnier H, Micheau C, Saravane D, Cachin Y. Prognostic factors in cervical lymph node metastasis in upper respiratory and digestive tract carcinomas: study of 1,713 cases during a 15-year period. Laryngoscope. 1987;97:97–101.PubMedCrossRef
15.
go back to reference Ferlito A, Rinaldo A, Devaney KO, et al. Prognostic significance of microscopic and macroscopic extracapsular spread from metastatic tumor in the cervical lymph nodes. Oral Oncol. 2002;38:747–51.PubMedCrossRef Ferlito A, Rinaldo A, Devaney KO, et al. Prognostic significance of microscopic and macroscopic extracapsular spread from metastatic tumor in the cervical lymph nodes. Oral Oncol. 2002;38:747–51.PubMedCrossRef
16.
go back to reference Dobi E, Bazan F, Dufresne A, et al. Is extracapsular tumour spread a prognostic factor in patients with early breast cancer? Int J Clin Oncol. 2013;18:607–13.PubMedCrossRef Dobi E, Bazan F, Dufresne A, et al. Is extracapsular tumour spread a prognostic factor in patients with early breast cancer? Int J Clin Oncol. 2013;18:607–13.PubMedCrossRef
17.
go back to reference Alakus H, Holscher AH, Grass G, et al. Extracapsular lymph node spread: a new prognostic factor in gastric cancer. Cancer. 2010;116:309–15.PubMedCrossRef Alakus H, Holscher AH, Grass G, et al. Extracapsular lymph node spread: a new prognostic factor in gastric cancer. Cancer. 2010;116:309–15.PubMedCrossRef
18.
go back to reference Nakamura K, Ozaki N, Yamada T, et al. Evaluation of prognostic significance in extracapsular spread of lymph node metastasis in patients with gastric cancer. Surgery. 2005;137:511–7.PubMedCrossRef Nakamura K, Ozaki N, Yamada T, et al. Evaluation of prognostic significance in extracapsular spread of lymph node metastasis in patients with gastric cancer. Surgery. 2005;137:511–7.PubMedCrossRef
19.
go back to reference Myers JN, Greenberg JS, Mo V, Roberts D. Extracapsular spread. A significant predictor of treatment failure in patients with squamous cell carcinoma of the tongue. Cancer. 2001;92:3030–6.PubMedCrossRef Myers JN, Greenberg JS, Mo V, Roberts D. Extracapsular spread. A significant predictor of treatment failure in patients with squamous cell carcinoma of the tongue. Cancer. 2001;92:3030–6.PubMedCrossRef
20.
go back to reference Liao CT, Lee LY, Huang SF, et al. Outcome analysis of patients with oral cavity cancer and extracapsular spread in neck lymph nodes. Int J Radiat Oncol Biol Phys. 2011;81:930–7.PubMedCrossRef Liao CT, Lee LY, Huang SF, et al. Outcome analysis of patients with oral cavity cancer and extracapsular spread in neck lymph nodes. Int J Radiat Oncol Biol Phys. 2011;81:930–7.PubMedCrossRef
21.
go back to reference Michikawa C, Uzawa N, Sato H, Ohyama Y, Okada N, Amagasa T. Epidermal growth factor receptor gene copy number aberration at the primary tumour is significantly associated with extracapsular spread in oral cancer. Br J Cancer. 2011;104:850–5.PubMedCentralPubMedCrossRef Michikawa C, Uzawa N, Sato H, Ohyama Y, Okada N, Amagasa T. Epidermal growth factor receptor gene copy number aberration at the primary tumour is significantly associated with extracapsular spread in oral cancer. Br J Cancer. 2011;104:850–5.PubMedCentralPubMedCrossRef
22.
go back to reference Prim MP, De Diego JI, Hardisson D, Madero R, Nistal M, Gavilan J. Extracapsular spread and desmoplastic pattern in neck lymph nodes: two prognostic factors of laryngeal cancer. Ann Otol Rhinol Laryngol. 1999;108:672–6.PubMed Prim MP, De Diego JI, Hardisson D, Madero R, Nistal M, Gavilan J. Extracapsular spread and desmoplastic pattern in neck lymph nodes: two prognostic factors of laryngeal cancer. Ann Otol Rhinol Laryngol. 1999;108:672–6.PubMed
23.
go back to reference Kuhnt T, Klockenbrink U, Knipping S, et al. Adjuvant low single dose cisplatin-based concurrent radiochemotherapy of oral cavity and oropharynx carcinoma: impact of extracapsular nodal spread on distant metastases. Strahlenther Onkol 2011;187:292–9.PubMedCrossRef Kuhnt T, Klockenbrink U, Knipping S, et al. Adjuvant low single dose cisplatin-based concurrent radiochemotherapy of oral cavity and oropharynx carcinoma: impact of extracapsular nodal spread on distant metastases. Strahlenther Onkol 2011;187:292–9.PubMedCrossRef
24.
go back to reference Woolgar JA, Rogers S, West CR, Errington RD, Brown JS, Vaughan ED. Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection. Oral Oncol. 1999;35:257–65.PubMedCrossRef Woolgar JA, Rogers S, West CR, Errington RD, Brown JS, Vaughan ED. Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection. Oral Oncol. 1999;35:257–65.PubMedCrossRef
25.
go back to reference Rogers SN, Brown JS, Woolgar JA, et al. Survival following primary surgery for oral cancer. Oral Oncol. 2009;45:201–11.PubMedCrossRef Rogers SN, Brown JS, Woolgar JA, et al. Survival following primary surgery for oral cancer. Oral Oncol. 2009;45:201–11.PubMedCrossRef
26.
go back to reference Woolgar JA, Rogers SN, Lowe D, Brown JS, Vaughan ED. Cervical lymph node metastasis in oral cancer: the importance of even microscopic extracapsular spread. Oral Oncol. 2003;39:130–7.PubMedCrossRef Woolgar JA, Rogers SN, Lowe D, Brown JS, Vaughan ED. Cervical lymph node metastasis in oral cancer: the importance of even microscopic extracapsular spread. Oral Oncol. 2003;39:130–7.PubMedCrossRef
27.
go back to reference Hellman S, Karnofsky Memorial Lecture. Natural history of small breast cancers. J Clin Oncol. 1994;12:2229–34.PubMed Hellman S, Karnofsky Memorial Lecture. Natural history of small breast cancers. J Clin Oncol. 1994;12:2229–34.PubMed
28.
go back to reference Kawada K, Taketo MM. Significance and mechanism of lymph node metastasis in cancer progression. Cancer Res. 2011;71:1214–8.PubMedCrossRef Kawada K, Taketo MM. Significance and mechanism of lymph node metastasis in cancer progression. Cancer Res. 2011;71:1214–8.PubMedCrossRef
29.
go back to reference Kim JM, Kim HJ, Koo BS, Rha KS, Yoon YH. Expression of matrix metalloproteinase-12 is correlated with extracapsular spread of tumor from nodes with metastasis in head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol. 2013;270:1137–42.PubMedCrossRef Kim JM, Kim HJ, Koo BS, Rha KS, Yoon YH. Expression of matrix metalloproteinase-12 is correlated with extracapsular spread of tumor from nodes with metastasis in head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol. 2013;270:1137–42.PubMedCrossRef
30.
go back to reference Brennan PA, Dennis S, Poller D, Quintero M, Puxeddu R, Thomas GJ. Inducible nitric oxide synthase: correlation with extracapsular spread and enhancement of tumor cell binvasion in head and neck squamous cell carcinoma. Head Neck. 2008;30:208–14.PubMedCrossRef Brennan PA, Dennis S, Poller D, Quintero M, Puxeddu R, Thomas GJ. Inducible nitric oxide synthase: correlation with extracapsular spread and enhancement of tumor cell binvasion in head and neck squamous cell carcinoma. Head Neck. 2008;30:208–14.PubMedCrossRef
31.
go back to reference Zhou X, Temam S, Oh M, et al. Global expression-based classification of lymph node metastasis and extracapsular spread of oral tongue squamous cell carcinoma. Neoplasia. 2006;8:925–32.PubMedCentralPubMedCrossRef Zhou X, Temam S, Oh M, et al. Global expression-based classification of lymph node metastasis and extracapsular spread of oral tongue squamous cell carcinoma. Neoplasia. 2006;8:925–32.PubMedCentralPubMedCrossRef
33.
go back to reference Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.PubMedCrossRef Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.PubMedCrossRef
35.
go back to reference Gunasinghe NP, Wells A, Thompson EW, Hugo HJ. Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer. Cancer Metastasis Rev. 2012;31:469–78.PubMedCrossRef Gunasinghe NP, Wells A, Thompson EW, Hugo HJ. Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer. Cancer Metastasis Rev. 2012;31:469–78.PubMedCrossRef
36.
go back to reference Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB. Regional lymph node involvement and its significance in the development of distant metastases in head and neck carcinoma. Cancer. 1993;71:452–6.PubMedCrossRef Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB. Regional lymph node involvement and its significance in the development of distant metastases in head and neck carcinoma. Cancer. 1993;71:452–6.PubMedCrossRef
37.
go back to reference Carter RL, Barr LC, O’Brien CJ, Soo KC, Shaw HJ. Transcapsular spread of metastatic squamous cell carcinoma from cervical lymph nodes. Am J Surg. 1985;150:495–9.PubMedCrossRef Carter RL, Barr LC, O’Brien CJ, Soo KC, Shaw HJ. Transcapsular spread of metastatic squamous cell carcinoma from cervical lymph nodes. Am J Surg. 1985;150:495–9.PubMedCrossRef
38.
go back to reference Ferlito A, Rinaldo A, Buckley JG, Mondin V. General considerations on distant metastases from head and neck cancer. ORL J Otorhinolaryngol Relat Spec. 2001;63:189–91.PubMedCrossRef Ferlito A, Rinaldo A, Buckley JG, Mondin V. General considerations on distant metastases from head and neck cancer. ORL J Otorhinolaryngol Relat Spec. 2001;63:189–91.PubMedCrossRef
39.
go back to reference Ichii S, Imai Y, Irimura T. Initial steps in lymph node metastasis formation in an experimental system: possible involvement of recognition by macrophage C-type lectins. Cancer Immunol Immunother. 2000;49:1–9.PubMedCrossRef Ichii S, Imai Y, Irimura T. Initial steps in lymph node metastasis formation in an experimental system: possible involvement of recognition by macrophage C-type lectins. Cancer Immunol Immunother. 2000;49:1–9.PubMedCrossRef
40.
go back to reference Cady B. Regional lymph node metastases; a singular manifestation of the process of clinical metastases in cancer: contemporary animal research and clinical reports suggest unifying concepts. Ann Surg Oncol. 2007;14:1790–800.PubMedCrossRef Cady B. Regional lymph node metastases; a singular manifestation of the process of clinical metastases in cancer: contemporary animal research and clinical reports suggest unifying concepts. Ann Surg Oncol. 2007;14:1790–800.PubMedCrossRef
Metadata
Title
Prognostic Significance of Epithelial-Mesenchymal Transition of Extracapsular Spread Tumors in Lymph Node Metastases of Head and Neck Cancer
Authors
Won-Yong Lee, MD
Da-Yong Shin, MS
Hye Jin Kim, MS
Young-Hyeh Ko, MD, PhD
Sehoon Kim, PhD
Han-Sin Jeong, MD, PhD
Publication date
01-06-2014
Publisher
Springer US
Published in
Annals of Surgical Oncology / Issue 6/2014
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-014-3567-z

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